This invention relates to a culture producing zaragozic acid A, and a compound of the formula I below. It also relates to a composition for the treatment of fungal infections and hypercholesterolemia comprising the compound I, and the use of such compound in the treatment of fungal infections, hypercholesterolemia, and in cancer chemotherapy.
The risk of coronary disease may be reduced by lowering the serum cholesterol level. In the biosynthesis of cholesterol, squalene synthase plays a critical role in combining two units of farnesyl diphosphate into squalene which is a penultimate precursor of sterols. Zaragozic acid A, a known squalene synthase inhibitor, also known as squalestatin 1, is reportedly produced by an unidentified culture ATCC 20986, Phoma sp. C2932, Curvularia lunata, Exserohilum rostratum and Setosphaeria khartoumensis. Other known squalene synthase inhibitors are zaragozic acid B and C which are produced by Sporormiella intermedia and Leptodontium elatius, respectively; squalestatin 2 and 3 are also produced by Phoma sp. C2932.
In cancer chemotherapy, inhibitors of ras farnesylation have been sought, based on the observation that farnesylation is critical for ras protein to localize onto the cytosolic membrane. Interference of the function of mutated ras protein is considered to provide a novel cancer therapy. Zaragozic acid A has been shown to inhibit farnesylation of ras protein. More recently, several peptidominmetic compounds have been disclosed as inhibitors of ras farnesyltransferase.